PATHWAYS OF BLADDER TUMORIGENESIS

产品描述：项目4的长期目标是通过测试有两种途径可以产生膀胱肿瘤的假设来了解膀胱肿瘤发生的分子基础。第一种是p16参与的，经常产生有复发倾向的浅表乳头状肿瘤，但不太可能进展。第二种涉及p53，以原位癌开始并经常进展。为了实现这一目标，我们将在转基因小鼠中开发肿瘤发生的模型系统，其中包含在人类移行细胞癌中经常观察到的致癌改变。对这种定制系统的需要来自于以下事实：尽管膀胱肿瘤已经通过化学试剂实验性地产生，但是触发这种肿瘤的分子机制通常是未知的，并且在已经分析它们的情况下，它们很少模拟在人移行细胞癌中看到的致癌事件，即，表皮生长因子受体（EGFR）、H-ras、p16和p53的变化。直到最近，还不可能将基因的表达特异性地导向尿道。然而，最近的分离，这样的尿路上皮特异性启动子，从uroplakin II（UPII）基因，将使我们能够产生转基因小鼠品系与特定的致癌变化的尿路上皮。因此，我们将使用UPII启动子来驱动正常和活化的EGFR、活化的H-ras和p53的显性负突变体的尿路上皮表达。我们还将利用cre/loxP系统特异性地阻断小鼠尿道上皮中的p53和p16。将检查这些转基因对尿路上皮生长和肿瘤形成的影响。为了使肿瘤产量最大化，这些基因也将以特定的组合使用，如果必要的话，与亚致癌剂量的膀胱致癌物一起使用。为了评估这些改变在膀胱肿瘤中的关键作用，我们将分析是否激活了适当的通路。这些肿瘤发生的模型系统和膀胱癌发病机制的双途径假说的测试将导致更好地了解膀胱肿瘤的发病机制，它也可能有助于更明智的治疗人类移行细胞癌。

Description: (Taken directly from the application) The long term goal of Project 4 is to understand the molecular basis of bladder tumorigenesis by testing the hypothesis that there are two pathways that can produce a bladder tumor. The first, where p16 is involved, frequently produces superficial papillary tumors with a tendency to recur, but unlikely to progress. The second, which involves p53, starts as a carcinoma in situ and frequently progresses. Towards this goal, we will develop model systems of tumorigenesis in transgenic mice, which contain oncogenetic alterations frequently observed in human transitional cell carcinoma. The need for such tailored system comes from the fact that, although bladder tumors have been experimentally produced by chemical agents, the molecular mechanisms triggering such tumors are frequently unknown, and in the cases where they have been analyzed, they rarely mimic the oncogenic events seen in human transitional cell carcinomas, i.e., changes in epidermal growth factor receptor (EGFR), H-ras, p16 and p53. Until recently, it had been impossible to direct the expression of a gene specifically to the urothelium. However, the recent isolation of such a urothelial specific promoter, from the uroplakin II (UPII) gene, will enable us to generate transgenic mouse lines with specific oncogenic changes in the urothelium. We will therefore use the UPII promoter to drive the urothelial expression of normal and activated EGFR, activated H-ras, and a dominant negative mutant of p53. We will also utilize the cre/loxP system to specifically inactivate p53 and p16 in the mouse urothelium. The effects of these transgenes on urothelial growth and tumor formation will be examined. To maximize the tumor yield, the genes will also be used in specific combinations and, if necessary, together with subcarcinogenic doses of bladder carcinogens. To assess the crucial role of these alterations in the bladder tumors, we will analyze if the appropriate pathways are activated. These model systems of tumorigenesis and the test of the two pathway hypothesis of bladder cancer pathogenesis should lead to a better understanding of the pathogenesis of bladder tumors, and it may also contribute to a more informed therapy of human transitional cell carcinoma.